European Journal of Pharmacology, 145 (1988) 323-327 323 Elsevier EJP 50080 Conditioning of the early behavioral response to apomorphine in the rotational model of Parkinson's disease E. Burunat 1,., R. Castro 2, M.D. Diaz-Palarea 2 and M. Rodriguez 2 1 Department of Psychobiology, School of Psychology, and 2 Department of Physiology, School of Medicine, University of La Laguna, Canary Islands, Spain Received 6 October 1987, accepted 20 October 1987 The rotational model of Parkinson's disease has been widely used to investigate the action of dopamine agonists. This animal model involves the production of a unilateral nigrostriatal lesion in rats. The lesion is produced with 6-hydroxydopamine which causes dopamine depletion and subsequent supersensitivity of striatal receptors. Thus, administration of drugs which are therapeutically effective in Parkinson's disease, elicits circling behavior contralateral to the lesioned side. The origin of the paradoxical response and the undrugged rotations observed after saline injections in apomorphine pretreated rats has not been explained. We report here that the undrugged response can be associated with the early rotational response elicited by the drug. Furthermore, we show the effect of inhibitory conditioning on this early response. Our results suggest that pharmacological conditioning plays a significant role in the modification of the therapeutic effectiveness of CNS-active drugs after extended treatments. Apomorphine; Parkinson's disease; Pharmacological conditioning; (Rotational model, Early response) 1. Introduction Unilateral 6-hydroxydopamine-induced degen- eration of the nigrostnatal system results in the development of receptor supersensitivity in the ipsilateral striatum. The administration of levo- dopa and direct-acting dopamine receptor agonists such as apomorphine and bromocnptine to rats lesioned in this way causes contralateral circling behaviour (Ungerstedt, 1971; Marshall and Un- gerstedt, 1977; Hefti et al., 1979; Hefti et al., 1980). An unexplained effect of apomorphine in this model is the spontaneous circling behavior that animals show when they are placed in the environ- ment where they previously experienced the ef- fects of apomorphine. This 'paradoxical' response (Ungerstedt, 1976) or 'undrugged' response after vehicle injection (Silverman and Ho, 1981) has not previously been related to the behavioral response to the drug. We related the undrugged response to saline (in 6-OHDA-lesioned and apomorphine-treated animals) with the early response to the drug. Fur- thermore, we demonstrate, with the use of an inhibitory conditioning design, that this early re- sponse is a conditioned response that develops during drug treatment. 2. Materials and methods 2.1. Animals * To whom all correspondence should be addressed: Area de Psicobiologia, Seccion de Psicologia, Facultad de Filosofia y CC. de la E., Universidad de la Laguna, Tenerife, Islas Canarias. Experiments were carried out on male Sprague- Dawley rats (Panlab, Barcelona) weighing 200-250 g. The animals were housed under normal labora- 0014-2999/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)